Individuals infected with the human immunodeficiency virus (HIV) develop a degenerative disease of the immune and central nervous systems that is accompanied by a broad spectrum of opportunistic infections. How HIV causes these degeneration is unknown. Studies with SIV indicate that nef plays an important role in vivo for the maintenance of high virus load and the development of AIDS. These observations make nef a good target for drug development against AIDS. Our previous and current efforts have been to study the molecular basis of Nef function. We have developed a system tO study the molecular basis of Nef-induced cell surface CD4 downregulation and determined that the cytoplasmic tail of CD4 is required for its downmodulation by Nef. We have also shown that pathogenic isolates of Nef from both HIV-1 and SIV suppress CD4 expression. To determine if this conserved function of Nef is important in HIV pathogenesis we will correlate Nef function with disease progression and virus replication in vivo. This will be accomplished by a functional analysis of nef genes isolated from patients at different stages of disease and by comparing the ability of viruses containing wild type or mutant nef alleles which do not downmodulate CD4 expression to replicate in vivo. We also propose to determine possible therapeutic targets to inhibit Nef function by a) determining the mechanism of Nef action and b) identifying posttranslational modifications essential for Nef function. Our long term goal is to use our understanding of Nef function to develop inhibitors which by interfering with Nef could block progression to AIDS in HIV infected individuals.